U.S. patent application number 10/050005 was filed with the patent office on 2002-07-18 for bicyclic aryl carboxamides and their therapeutic use.
Invention is credited to Dyke, Hazel Joan, Montana, John Gary.
Application Number | 20020094987 10/050005 |
Document ID | / |
Family ID | 26310411 |
Filed Date | 2002-07-18 |
United States Patent
Application |
20020094987 |
Kind Code |
A1 |
Dyke, Hazel Joan ; et
al. |
July 18, 2002 |
Bicyclic aryl carboxamides and their therapeutic use
Abstract
Compounds of the formula (i) 1 have therapeutic utility via
inhibition of TNF or phosphodiesterase.
Inventors: |
Dyke, Hazel Joan;
(Cambridge, GB) ; Montana, John Gary; (Cambridge,
GB) |
Correspondence
Address: |
SALIWANCHIK LLOYD & SALIWANCHIK
A PROFESSIONAL ASSOCIATION
2421 N.W. 41ST STREET
SUITE A-1
GAINESVILLE
FL
326066669
|
Family ID: |
26310411 |
Appl. No.: |
10/050005 |
Filed: |
January 14, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10050005 |
Jan 14, 2002 |
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09422473 |
Oct 21, 1999 |
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6353010 |
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09422473 |
Oct 21, 1999 |
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08971806 |
Nov 17, 1997 |
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Current U.S.
Class: |
514/249 ;
514/266.1; 514/266.2; 544/231; 544/283; 544/284; 544/353 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 19/00 20180101; C07D 401/12 20130101; A61P 43/00 20180101;
C07D 417/14 20130101; A61P 1/00 20180101; A61P 9/00 20180101; A61P
11/00 20180101; A61P 35/00 20180101; A61P 29/00 20180101; A61P 7/00
20180101; A61P 13/00 20180101; C07D 413/12 20130101; A61P 11/06
20180101; A61P 17/00 20180101; A61P 25/28 20180101; A61P 27/00
20180101; A61P 37/00 20180101; A61P 31/00 20180101; C07D 413/14
20130101 |
Class at
Publication: |
514/249 ;
514/266.1; 514/266.2; 544/231; 544/283; 544/284; 544/353 |
International
Class: |
A61K 031/517; A61K
031/498; C07D 239/72 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 15, 1996 |
GB |
9623860.5 |
Apr 22, 1997 |
GB |
9708062.6 |
Claims
1. A compound of the general formula (i) 6wherein (1) X is N and
(a) Z is .dbd.CR.sub.1--CR.sub.2.dbd. and Y is N, or (b) Z is
.dbd.CR.sub.1 and Y is NR.sub.4, or (c) Z is .dbd.CR.sub.1--N.dbd.
and Y is CR.sub.2; or (2) X is NR.sub.4, Z is CR.sub.1.dbd., and Y
is N; Q is selected from the group consisting of O and S; R.sub.1
and R.sub.2 are the same or different and are each selected from
the group consisting of COR.sub.6, C(.dbd.NOR.sub.6)R.sub.13,
alkyl-C(.dbd.NOR.sub.6)R.sub.13, NR.sub.8R.sub.9,
CON(R.sub.6).sub.2, halogen, CF.sub.3, CN, CO.sub.2H,
CO.sub.2R.sub.10, R.sub.6, CO-het where het is a heterocyclic ring
attached via a N atom in the ring and optionally substituted with
one or more R.sub.14, or the cyclic group 7R.sub.3 is selected from
the group consisting of OH, thioalkyl, and C.sub.1-6 alkoxy or
cycloalkoxy each optionally substituted with one or more halogens;
R.sub.4 is selected from the group consisting of H and alkyl;
R.sub.5 is aryl or heteroaryl (or an N-oxide thereof), either of
which may be optionally substituted with one or more substituents
selected from the group consisting of halogen, optionally
halogen-substituted alkyl, hydroxy, optionally halogen-substituted
alkoxy, CO.sub.2H, CO.sub.2R.sub.10, CONR.sub.11R.sub.12,
COR.sub.10, SO.sub.2R.sub.10, SO.sub.2NR.sub.11R.sub.12,
NR.sub.8R.sub.9, and CN; each R.sub.6 is independently selected
from the group consisting of H, alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, and
heterocycloalkyl, any of which groups is optionally substituted at
any position with R.sub.7; R.sub.7 is selected from the group
consisting of alkyl, hydroxy, OR.sub.10, NR.sub.8R.sub.9, CN,
CO.sub.2H, CO.sub.2R.sub.10, CONR.sub.11R.sub.12, and COR.sub.10;
R.sub.8 is selected from the group consisting of H, alkyl,
cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,
heteroarylalkyl, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl,
arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl,
alkylsulphonyl, arylsulphonyl, heteroarylsulphonyl, and
heterocyclosulphonyl; R.sub.9 is selected from the group consisting
of H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl,
heteroarylalkyl, and heterocycloalkyl; or NR.sub.8R.sub.9 is a
heterocyclic ring optionally substituted with R.sub.14; R.sub.10 is
selected from the group consisting of alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, and
heterocycloalkyl; R.sub.11 and R.sub.12 are the same or different
and are each H or R.sub.10; R.sub.13 is R.sub.10 optionally
substituted with one or more R.sub.7; R.sub.14 is selected from the
group consisting of alkyl, arylalkyl, and heteroarylalkyl; and
R.sub.15 is alkyl; V is O or S, and n=2-4; or a
pharmaceutically-acceptable salt thereof.
2. The compound according to claim 1, wherein R.sub.3 is
methoxy.
3. The compound according to claim 1, wherein R.sub.4 is H.
4. The compound according to claim 2, wherein R.sub.4 is H.
5. The compound according to claim 1, wherein R.sub.5 is
optionally-substituted 4-pyridyl or optionally-substituted
4-pyridyl-N-oxide.
6. The compound according to claim 1, wherein R.sub.1 and R.sub.2
are independently selected from the group consisting of COR.sub.6,
C(.dbd.NOR.sub.6)R.sub.13, CF.sub.3, CN, R.sub.6, and said cyclic
group.
7. The compound according to claim 1, wherein R.sub.1 and R.sub.2
are the same or different and are each selected from the group
consisting of COR.sub.6, C(.dbd.NOR.sub.6)R.sub.13,
alkyl-C(.dbd.NOR.sub.6)R.sub.13, NR.sub.8R.sub.9,
CON(R.sub.13).sub.2, halogen, CF.sub.3, CN, CO.sub.2H,
CO.sub.2R.sub.10, and R.sub.6; R.sub.3 is selected from the group
consisting of OH, thioalkyl, and optionally-substituted alkoxy;
R.sub.5 is aryl or heteroaryl, either of which may be optionally
substituted with one or more substituents selected from the group
consisting of halogen, alkyl, hydroxy, alkoxy, CO.sub.2H,
CO.sub.2R.sub.10, CONR.sub.11R.sub.12, COR.sub.10,
SO.sub.2R.sub.10, SO.sub.2NR.sub.11R.sub.12, NR.sub.8R.sub.9, and
CN; R.sub.7 is not alkyl; and R.sub.8 and R.sub.9 are
independent.
8. The compound according to claim 1, wherein Q is O; R.sub.1 and
R.sub.2 are the same or different and are each selected from the
group consisting of COR.sub.13, C(.dbd.NOR.sub.10)R.sub.13, CN,
CO.sub.2H, CO.sub.2R.sub.10, CONR.sub.11R.sub.12, and R.sub.6;
R.sub.3 is C.sub.1-6 optionally substituted with one or more
halogens; R.sub.6 is selected from the group consisting of H,
alkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl,
and heterocycloalkyl, any of which groups is optionally substituted
at any position with R.sub.7; R.sub.10 is selected from the group
consisting of alkyl, aryl, heteroaryl, heterocyclo, arylalkyl,
heteroarylalkyl, and heterocycloalkyl; and R.sub.11 and R.sub.12
are the same or different and are each H or R.sub.10.
9. The compound according to claim 1, which is
8-methoxyquinoxaline-5-[N-(-
2,6-dichloropyrid-4-yl)]carboxamide.
10. The compound according to claim 1, which is
2-trifluoromethyl-3-methyl-
-7-methoxybenzimidazole-4-[N-(3,5-dichloropyrid-4-yl)]carboxamide.
11. The compound according to claim 1, selected from the group
consisting of
2-acetyl-7-methoxy-3-methylbenzimidazole-4-[N-(pyridin-4-yl)]carboxami-
de;
7-methoxy-3-propyl-2-trifluoromethylbenzimidazole-4-[N-(3,5-dichloropy-
ridin-4-yl)]carboxamide;
2-acetyl-7-methoxy-3-methylbenzimidazole-4-[N-3,5-
-dichloropyrid-4-yl)]carboxamide;
7-methoxy-3-(4-methoxybenzyl)-2-trifluor-
omethylbenzimidazole-4-[N-(3,5-dichloropyridin-4-yl)]carboxamide;
N-(3,5-dichloropyrid-4-yl)-7-methoxy-2-trifluoromethylbenzimidazole-4-car-
boxamide;
2-(1-hydroxyimino)ethyl-7-methoxy-3-methyl-benzimidazole-4-[N-3,-
5-dichloropyridyl)]carboxamide;
3-methyl-2-1-(2-methylthiazol-4-ylmethoxy)-
iminoethyl)-7-methoxybenzimidazole-4-[N-(3,5-dichloropyrid-4-yl)]carboxami-
de; and
3-methyl-2-]1-(3-dimethylaminopropyloxy)iminoethyl]-7-methoxybenzi-
midazole-4-[N-(3,5-dichloropyrid-4-yl)]carboxamide.
12. The compound according to claim 1, wherein said compound is in
the form of an enantiomer.
13. A pharmaceutical composition for therapeutic use comprising a
compound of claim 1 and a pharmaceutically-acceptable carrier or
excipient.
14. A method for treating a disease state capable of being
modulated by inhibition of phosphodiesterase IV or Tumour Necrosis
Factor, or that is a pathological condition associated with a
function of phosphodiesterase IV, eosinophil accumulation, or a
function of the eosinophil, wherein said method comprises
administration to a human or animal in need of such treatment an
effective amount of a compound of claim 1.
15. The method according to claim 14, wherein said disease state is
an inflammatory disease or an autoimmune disease.
16. The method according to claim 14, wherein said disease state is
selected from the group consisting of asthma, chronic bronchitis,
chronic pulmonary inflammatory disease, chronic obstructive airways
disease, atopic dermatitis, allergic rhinitis, psoriasis,
arthritis, rheumatoid arthritis, joint inflammation, ulcerative
colitis, Crohn's disease, atopic eczema, stroke, bone resorption
disease, multiple sclerosis, and inflammatory bowel disease.
17. The method according to claim 14, wherein said disease state is
selected from the group consisting of urticaria, allergic
conjunctivitis, vernal conjunctivitis, inflammation of the eye,
allergic responses in the eye, eosinophilic granuloma, gouty
arthritis and other arthritic conditions, adult respiratory
distress syndrome, diabetes insipidus, keratosis, cerebral
senility, multi-infarct dementia, senile dementia, memory
impairment associated with Parkinson's disease, depression, cardiac
arrest, intermittent claudication, rheumatoid spondylitis,
osteoarthritis, sepsis, septic shock, endotoxin shock, gram
negative sepsis, toxic shock syndrome, cerebral malaria, silicosis,
pulmonary sarcoidosis, reperfusion injury, graft vs. host reaction.
allograft rejection, infection-related fever or myalgia, malaria,
HIV, AIDS, ARC, cachexia, keloid formation, scar tissue formation,
pyresis, systemic lupus erythematosus, type I diabetes mellitus,
Bechet's disease, anaphylactoid purpura nephritis, chronic
glomerulonephritis, leukaemia, tarditive dyskensia, yeast or fungal
infection, conditions requiring gastroprotection, and neurogenic
inflammatory disease associated with irritation and pain.
18. The method according to claim 14, wherein said disease state is
asthma.
19. The method according to claim 14, wherein said disease state is
selected from the group consisting of chronic obstructive airways
disease, chronic bronchitis, and chronic pulmonary inflammatory
disease.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel heterocyclic
compounds and pharmaceutically-acceptable salts thereof, processes
for their production and formulation and use as
pharmaceuticals.
BACKGROUND OF THE INVENTION
[0002] 2-Thienylbenzoxazoles with anti-aggregating activity are
described in Eur. J. Med. Chem. (1994) 29:75.
[0003] EP-A-0116938 and J. Med. Chem. (1987) 30 62 describe
heteroaryloxycarboxamides as lipolysis inhibitors useful in the
treatment of ischemic heart disease and hypertriglyceridemia.
[0004] WO-A-9406783 and WO-A-9406782 describe
heteroarylsulphonamides having insecticidal, nematicidal,
acaricidal and fungicidal activity.
[0005] WO-A-9604251 describes aryloxy derivatives of heteroaryl
compounds as bradykinin inhibitors.
[0006] Heteroaryl compounds are described as fibrinogen antagonists
in WO-A-9408962,
[0007] EP-A-0498722 describes amide derivatives of heteroaryl
compounds.
[0008] Quinoxalines are disclosed as performance enhancers for
animals in EP-A-0456067.
[0009] Benzimidazoles are described as dopamine antagonists in
WO-A-9422839.
[0010] DE-A4237617 discloses imidazoles as antiparasitic
agents.
[0011] Phosphodiesterases (POE) and Tumour Necrosis Factor (TNF),
their modes of action and the therapeutic utilities of inhibitors
thereof, are described in WO-A-9720833 and PCI/GB97/01361, the
contents of which are incorporated herein by reference The same
documents disclose carboxamides having utility as PDE and TNF
inhibitors.
SUMMARY OF THE INVENTION
[0012] This invention is directed to the pharmaceutical use of a
compound of formula (i) below to treat disease states, for example
disease states associated with proteins which mediate cellular
activity, for example by inhibiting tumour necrosis factor and/or
by inhibiting phosphodiesterase IV. According to the invention,
novel compounds are of formula (i): 2
[0013] wherein
[0014] (1) X is N and (a) Z is .dbd.CR.sub.1--CR.sub.2.dbd. and Y
is N, (b) Z is CR.sub.1-- and Y is O, S or NR.sub.4, or (c) Z is
.dbd.CR.sub.1--N.dbd. and Y is CR.sup.2, or (2) X is NR.sub.4, Z is
--CR.sub.1.dbd. and Y is N;
[0015] Q is O or S;
[0016] R.sub.1 and R.sub.2 are the same or different and are each
COR.sub.6, C(.dbd.NOR.sub.6)R.sub.13,
alkyl-C(.dbd.NOR.sub.6)R.sub.13, NR.sub.8R.sub.9,
CON(R.sub.6).sub.2, halogen, CF.sub.3, CN, CO.sub.2H,
CO.sub.2R.sub.10, R.sub.6, CO-het where het is a heterocyclic ring
(such as morpholine or piperidine) attached via a N atom in the
ring and optionally substituted with one or more R.sub.14, or 3
[0017] R.sub.3 is OH, thioalkyl, or C.sub.1-6 alkoxy or cycloalkoxy
each optionally substituted with one or more halogens;
[0018] R.sub.4 is H or alkyl;
[0019] R.sub.5 is aryl or heteroaryl, either of which may be
optionally substituted with one or more substituents chose from
halogen, optionally halogen-substituted alkyl, hydroxy, optionally
halogen-substituted alkoxy, CO.sub.2H, CO.sub.2R.sub.10,
CONR.sub.11R.sub.12, COR.sub.10, SO.sub.2R.sub.10,
SO.sub.2NR.sub.11R.sub.12, NR.sub.8R.sub.9 and CN;
[0020] each R.sub.6 is independently H or a group selected from
alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl,
heteroarylalkyl and heterocycloalkyl, any of which groups is
optionally substituted at any position with R.sub.7;
[0021] R.sub.7 is alkyl, hydroxy, OR.sub.10, NR.sub.8R.sub.9, CN,
CO.sub.2H, CO.sub.2R.sub.10, CONR.sub.11R.sub.12 or COR.sub.10;
[0022] R.sub.8 is H, alkyl, cycloalkyl, aryl, heteroaryl,
heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl,
alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, heteroarylcarbonyl,
heterocyclocarbonyl, alkylsulphonyl, arylsulphonyl,
heteroarylsulphonyl or heterocyclosulphonyl; R.sub.9 is H, alkyl,
cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroarylalkyl
or heterocycloalkyl; or NR.sub.8R.sub.9 is a heterocyclic ring
(such as morpholine or piperidine) optionally substituted with
R.sub.14;
[0023] R.sub.10 is alkyl, cycloalkyl, aryl, heteroaryl,
heterocyclo, arylalkyl, heteroarylalkyl or heterocycloalkyl;
[0024] R.sub.11 and R.sub.12 are the same or different and are each
H or R.sub.10;
[0025] R.sub.13 is R.sub.10 optionally substituted with one or more
R.sub.7;
[0026] R.sub.14 is alkyl, arylalkyl, and heteroarylalkyl; and
[0027] R.sub.15 is alkyl; V is O or S, and n is 2-4;
[0028] and pharmaceutically-acceptable salts thereof.
[0029] Compounds of the invention have a bicyclic aryl nucleus.
Depending on the definitions of X, Y and Z, they are (1a)
quinoxalines, (1b) benzoxazoles, benzthiazoles or benzimidazoles,
(1c) quinazolines or (2) benzimidazoles (differently substituted
from those under 1b). Preferred compounds are defined in the
subclaims.
DESCRIPTION OF THE INVENTION
[0030] Suitable pharmaceutically-acceptable salts are
pharmaceutically-acceptable base salts and
pharmaceutically-acceptable acid addition salts. Certain of the
compounds of formula (i) which contain an acidic group form base
salts. Suitable pharmaceutically-accept- able base salts include
metal salts, such as alkali metal salts for example sodium salts,
or organic amine salts such as that provided with
ethylenediamine.
[0031] Certain of the compounds of formula (i) which contain an
amino group form acid addition salts. Suitable acid addition salts
include pharmaceutically-acceptable inorganic salts such as the
sulphate, nitrate, phosphate, borate, hydrochloride and
hydrobromide and pharmaceutically-acceptable organic acid addition
salts such as acetate, tartrate, maleate, citrate, succinate,
benzoate, ascorbate, methane-sulphate, .alpha.-ketoglutarate,
.alpha.-glycerophosphate and glucose-1-phosphate. The
pharmaceutically-acceptable salts of the compounds of formula (i)
are prepared using conventional procedures.
[0032] It will be appreciated by those skilled in the art that some
of the compounds of formula (i) may exist in more than one
tautomeric form. This invention extends to all tautomeric forms. It
will be appreciated that the compounds according to the invention
can contain one or more asymmetrically substituted carbon atoms.
The presence of one or more of these asymmetric centers in a
compound of formula (i) can give rise to stereoisomers, and in each
case the invention is to be understood to extend to all such
stereoisomers, including enantiomers, and diastereoisomers and
mixtures including racemic mixtures thereof.
[0033] When used herein the term alkyl whether used alone or when
used as a part of another group includes straight and branched
chain alkyl groups containing up to 6 atoms. Alkoxy means an
alkyl-O-- group in which the alkyl group is as previously
described. Cycloalkyl includes a non-aromatic cyclic or multicyclic
ring system of about 3 to 10 carbon atoms. The cyclic alkyl may
optionally be partially unsaturated. Cycloalkoxy means a
cycloalkyl-I-group in which cycloalkyl is as defined above. Aryl
indicates an aromatic monocyclic or multicyclic carbocyclic group
containing about 6 to 10 carbon atoms. Arylalkyl means an
aryl-alkyl- group wherein the aryl and alkyl are as described
herein. Heteroarylalkyl means a heteroaryl-alkyl group and
heterocycloalkyl means a heterocycloalkyl group. Alkylcarbonyl
means an alkyl-CO-- group in which the alkyl group is as previously
described. Arylcarbonyl means an aryl-CO-- group in which the aryl
group is as previously described. Heteroarylcarbonyl means a
heteroaryl-CO-- group and heterocyclocarbonyl means a
heterocyclo-CO-- group. Arylsulphonyl means an aryl-SO.sub.2--
group in which the aryl group is as previously described.
Heteroarylsulphonyl means a heteroaryl-SO.sub.2-- group and
heterocyclosulphonyl means a heterocyclo-SO.sub.2-- group.
Alkoxycarbonyl means an alkyloxy-CO-- group in which the alkoxy
group is as previously described. Alkylsulphonyl means an
alkyl-SO.sub.2-- group in which the alkyl group is as previously
described. Heterocyclic ring means about a 5 to about a 10 membered
monocyclic or multicyclic ring system (which may saturated or
partially unsaturated) wherein one or more of the atoms in the ring
system is an element other than carbon chosen from amongst
nitrogen, oxygen or sulphur atoms. Heteroaryl means about a 5 to
about a 10 membered aromatic monocyclic or multicyclic hydrocarbon
ring system in which one or more of the atoms in the ring system is
an element other than carbon, chosen from amongst nitrogen, oxygen
or sulphur; if desired, a N atom may be in the form of an N-oxide.
Heterocyclo means about a 5 to about a 10 membered saturated or
partially saturated monocyclic or multicyclic hydrocarbon ring
system in which one or more of the atoms in the ring system is an
element other than carbon, chosen from amongst nitrogen, oxygen or
sulphur. Halogen means fluorine, chlorine, bromine or iodine.
[0034] "TNF mediated disease or disease states" means any and all
disease states in which TNF plays a role, either by production of
TNF itself, or by TNF causing another cytokine to be released, such
as but not limited to IL-1 or IL-6. A disease state in which IL-1,
for instance, is a major component, and whose production or action
is exacerbated or secreted in response to TNF, would therefore be
considered a disease state mediated by TNT. As TNF-.beta. (also
known as lymphotoxin) has close structural homology with
TNF-.alpha. (also known as cachectin), and since each induces
similar biologic responses and binds to the same cellular receptor,
both TNF-.alpha. and TNF-.beta. are inhibited by the compounds of
the present invention and thus are herein referred to collectively
as "TNF" unless specifically delineated otherwise.
[0035] This invention relates to a method for mediating or
inhibiting the enzymatic activity or catalytic activity of PDE IV
in a mammal in need thereof and for inhibiting the production of
TNF in a mammal in need thereof, which comprises administering to
said mammal an effective amount of a compound of Formula (i) or a
pharmaceutically-acceptable salt thereof
[0036] PDE IV inhibitors are useful in the treatment of a variety
of allergic and inflammatory diseases, including: asthma, chronic
bronchitis, chronic obstructive airways disease, chronic pulmonary
inflammatory disease, atopic dermatitis, atopic eczema, urticaria,
allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis,
inflammation of the eye, allergic responses in the eye,
eosinophilic granuloma, psoriasis, Bechet's disease, erythematosis,
anaphylactoid purpura nephritis, joint inflammation, arthritis,
rheumatoid arthritis and other arthritic conditions such as
rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative
colitis, Crohn's disease, reperfusion injury of the myocardium and
brain, chronic glomerulonephritis, endotoxic shock and adult
respiratory distress syndrome. In addition, PDE IV inhibitors are
useful in the treatment of diabetes insipidus and conditions
associated with cerebral metabolic inhibition, such as cerebral
senility, senile dementia (Alzheimer's disease), memory impairment
associated with Parkinson's disease, depression and multi-infarct
dementia. PDE IV inhibitors are also useful in conditions
ameliorated by neuroprotectant activity, such as cardiac arrest,
stroke and intermittent claudication. Additionally. PDE IV
inhibitors could have utility as gastroprotectants. A preferred
embodiment of the therapeutic methods of the present invention is
the treatment of asthma.
[0037] The viruses contemplated for treatment herein are those that
produce TNF as a result of infection, or those which are sensitive
to inhibition, such as by decreased replication, directly or
indirectly, by the TNF inhibitors of Formula (i). Such viruses
include, but are not limited to HIV-1, HIV-2 and HIV-3,
cytomegalovirus (CMV), influenza, adenovirus and the Hepes group of
viruses, such as, but not limited to, Herpes zoster and Herpes
simplex.
[0038] This invention more specifically relates to a method of
treating a mammal, afflicted with a human immunodeficiency virus
(HIV), which comprises administering to such mammal an effective
TNF inhibiting amount of a compound of Formula (i) or a
pharmaceutically-acceptable salt thereof.
[0039] The compounds of this invention may be also be used in
association with the veterinary treatment or animals other than
humans, in need of inhibition of TNF production. TNF mediated
diseases for treatment, therapeutically or prophylactically, in
animals include disease states such as those noted above, but in
particular viral infections. Examples of such viruses include, but
are not limited to feline immunodeficiency virus (FIV) or other
retroviral infection such as equine infectious anaemia virus,
caprine arthritis virus, visna virus, maedi virus and other
lentiviruses.
[0040] The compounds of this invention are also useful in treating
parasite, yeast and fungal infections, where such yeast and fungi
are sensitive to upregulation by TNF or will elicit TNF production
in vivo. A prefered disease state for treatment is fungal
meningitis.
[0041] The compounds of formula (i) are preferably in
pharmaceutically-acceptable form. By pharmaceutically-acceptable
form is meant, inter alia, of a pharmaceutically-acceptable level
of purity excluding normal pharmaceutical additives such as
diluents and carriers, and including no material considered toxic
at normal dosage levels. A pharmaceutically-acceptable level of
purity will generally be at least 50% excluding normal
pharmaceutical additives, preferably 75%, more preferably 90% and
still more preferably 95%.
[0042] The invention further provides a process for the preparation
of a compound of formula (i), in which R.sub.1-R.sub.15 and Q, X, Y
and Z are as defined above. It will be appreciated that functional
groups such as amino, hydroxyl or carboxyl groups present in the
various compounds described below, and which it is desired to
retain, may need to be in protected forms before any reaction is
initiated. In such instances, removal of the protecting group may
be the final step in a particular reaction. Suitable protecting
groups for such functionality will be apparent to those skilled in
the art. For specific details, see Protective Groups in Organic
Synthesis, Wiley Interscience, T W Greene. Thus a process for
preparing compounds of formula (i) in which R.sub.1 contains an
--OH comprises deprotecting (for example by hydrogenolysis or
hydrolysis) a compound of formula (i) in which R.sub.3 contains an
appropriate --OP wherein P represents a suitable protecting group
(eg benzyl).
[0043] A process for the preparation of a compound of formula (i)
comprises reaction of an appropriate carboxylic acid of formula
(ii) with a suitable amine of formula (iii) 4
[0044] wherein R.sub.3a represents R.sub.3 as defined in relation
to formula (i) or a group convertable to R.sub.3 and R.sub.4a and
R.sub.5a similarly represent R.sub.4 and R.sub.5 or groups
convertable to R.sub.4 and R.sub.5 respectively and X', Y' and Z'
represent Y, Y and Z or groups convertable to X, Y and Z
respectively; and thereafter, if required, converting any group
R.sub.3a to R.sub.3 and/or R.sub.4a to R.sub.4 and/or R.sub.5a to
R.sub.5 and/or X' to X and/or Y' to Y and/or Z' to Z. The reaction
of a carboxylic acid of formula (ii) with an amine of formula (iii)
may be carried out under any suitable conditions known to those
skilled in the art. Preferably, the carboxylic acid is converted
into an acid chloride, mixed anhydride or other activated
intermediate prior to reaction with an amine of formula (iii).
Preferably, the reaction with the amine of formula (iii) is carried
out in the presence of a suitable base, for example an amine base
such as triethylamine, preferably in an appropriate solvent such as
dichloromethane. In some cases a stronger base, such as sodium
hydride, and a polar solvent such as dimethylformamide, will be
required.
[0045] Carboxylic acids of formula (ii) are either commercially
available, previously described compounds or are prepared using
standard conditions known to those skilled in the art. For example,
a carboxylic acid of formula (ii) is conveniently prepared from a
compound of formula (iv), either by formylation to provide an
aldehyde of formula (v) followed by oxidation to provide the acid
of formula (ii), or by bromination to provide bromide of formula
(vi) followed by carboxylation to provide an acid of formula (ii).
5
[0046] Formylation of a compound of formula (iv) may be carried out
under standard conditions known to those skilled in the art, for
example by using phosphorous oxychloride and dimethylformamide at
elevated temperature. Oxidation of an aldehyde of formula (v) may
be carried out using appropriate conditions known to those skilled
in the art, for example by using sodium chlorite and sodium
phosphate in water/t-butanol in the presence of an acid scavenger
such as 2-methyl-2-butene. Bromination of a compound of formula
(iv) can be carried out using standard conditions, for example by
using bromine in an appropriate solvent such as methanol.
Carboxylation of a bromide of formula (vi) can conviently be
achieved by the use of an organometal catalyst, such as a palladium
catalyst in the presence of an appropriate base in a suitable
solvent.
[0047] A compound of formula (iv) may be commercially available, a
previously described compound or may be prepared using standard
conditions known to those skilled in the art. For example,
procedures are described in EP-A-0701907, EP-A-0116938,
DE-A-4237417, J. Med. Chem. (1987) 30 62, J. Chem. Soc. Perkin
Trans. I (1 982) 357 and J. Chem. Soc. Perkin Trans. I (1949) 3012,
J. Chem. Soc. (1928) 2393 and J. Chem. Soc. (1964) 4645.
[0048] Amines of formula (iii) are either commercially available,
previously described compounds or are prepared using standard
conditions known to those skilled in the art.
[0049] A compound of formula (i) may also be prepared by
interconversion of other compounds of formula (i). For example, a
compound in which R.sub.1 contains an alcohol function may be
prepared by reduction of a compound of formula (i) in which R.sub.1
contains a carbonyl function.
[0050] By way of further example, compounds in which R.sub.1 and/or
R.sub.2 contains an oxime may be prepared from compounds in which
R.sub.1 and/or R.sub.2 contain a carbonyl group. This
transformation may be carried out using any appropriate standard
conditions known to those skilled in the art. Compounds of formula
(i) in which R.sub.1 and/or R.sub.2 contain a carbonyl group may be
reduced using standard conditions known to those skilled in the art
(for example with sodium borohydride in an appropriate solvent) to
provide compounds in which R.sub.1 and/or R.sub.2 contains an
alcohol group. Compounds in which R.sub.1 and/or R.sub.2 is alkyl
may be prepared by reduction of compounds in which R.sub.1 and/or
R.sub.2 is CO-alkyl using standard conditions known to those
skilled in the art (for example hydrazine hydrate in the presence
of a suitable base in an appropriate solvent). Other
transformations may be carried out on compounds of formula (i) in
which R.sub.1 and/or R.sub.2 contains a carbonyl group. Such
transformations include, but are not limited to, reductive
amination and alkylation. Any of the above transformations may be
carried out either at the end of the synthesis or on an appropriate
intermediate. Compounds of formula (i) in which Z is CS may be
prepared from compounds of formula (i) in which Z is CO using any
appropriate conditions known to those skilled in the art, for
example by using Lawesson's reagent.
[0051] It will be appreciated that where a particular stereoisomer
of formula (i) is required, this may be obtained by conventional
resolution techniques such as high performance liquid
chromatography or the synthetic processes herein described may by
performed using the appropriate homochiral starting material.
[0052] A compound of formula (i) or where appropriate a
pharmaceutically-acceptable salt thereof and/or a
pharmaceutically-accept- able solvate thereof, may be administered
per se or, preferably, as a pharmaceutical composition also
comprising a pharmaceutically-acceptable carrier.
[0053] Accordingly, the present invention provides a pharmaceutical
composition comprising a compound of formula (i) or where
appropriate a pharmaceutically-acceptable salt thereof and/or a
pharmaceutically-accept- able solvate thereof, and a
pharmaceutically-acceptable carrier.
[0054] The active compound may be formulated for administration by
any suitable route, the preferred route depending upon the disorder
for which treatment is required, and is preferably in unit dosage
form or in a form that a human patient may administer to himself in
a single dosage. Advantageously, the composition is suitable for
oral, rectal, topical, parenteral administration or through the
respiratory tract. Preparations may be designed to give slow
release of the active ingredient.
[0055] The term parenteral as used herein includes subcutaneous
injections, intravenous, intramuscular, intrasternal injection or
infusion tecniques. In addition to the treatment of warm-blooded
animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc,
the compounds of the invention are effective in the treatment of
humans.
[0056] The compositions of the invention may be in the form of
tablets, capsules, sachets, vials, powders, granules, lozenges,
suppositories, reconstitutable powders, or liquid preparations such
as oral or sterile parenteral solutions or suspensions. Topical
formulations are also envisaged where appropriate.
[0057] In order to obtain consistency of administration it is
preferred that a composition of the invention is in the form of a
unit dose.
[0058] Unit dose presentation forms for oral administration may be
tablets and capsules and may contain conventional excipients such
as binding agents, for example syrup, acacia, gelatin, sorbitol,
tragacanth, or polyvinylpyrrolidone; fillers for example
microcrystalline cellulose, lactose, sugar, maize-starch, calcium
phosphate, sorbitol or glycine; tabletting lubricants, for example
magnesium stearate; disintegrants, for example starch,
polyvinylpyrrolidone, sodium starch glycolate or microcrystalline
cellulose; or pharmaceutically-acceptable wetting agents such as
sodium lauryl sulphate.
[0059] The solid oral compositions may be prepared by conventional
methods of blending, filling, tabletting or the like. Repeated
blending operations may be used to distribute the active agent
throughout those compositions employing large quantities of
fillers.
[0060] Such operations are of course conventional in the art. The
tablets may be coated according to methods well known in normal
pharmaceutical practice, in particular with an enteric coating.
[0061] Oral liquid preparations may be in the form of, for example,
emulsions, syrups or elixirs, or may be presented as a dry product
for reconstitution with water or other suitable vehicle before use.
Such liquid preparations may contain conventional additives such as
suspending agents, for example sorbitol, syrup, methyl cellulose,
gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium
stearate gel, hydrogenated edible fats; emulsifying agents, for
example lecithin, sorbitan monooleate, or acacia, non-aqueous
vehicles (which may include edible oils), for example almond oil,
fractionated coconut oil, oily esters such as esters of glycerine,
propylene glycol, or ethyl alcohol; preservatives, for example
methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired
conventional flavouring or colouring agents.
[0062] Compositions may also suitably be presented for
administration to the respiratory tract as a snuff or an aerosol or
solution for a nebuliser, or as a microfine powder for
insufflation, alone or in combination with an inert carrier such as
lactose. In such a case the particles of active compound suitably
have diameters of less than 50 microns, such as from 0.1 to 50
microns, preferably less than 10 microns, for example from 1 to 10
microns, 1 to 5 microns or from 2 to 5 microns. Where appropriate,
small amounts of other anti-asthmatics and bronchodilators for
example sympathomimetic amines such as isoprenaline, isoetharine,
salbutamol, phenylephrine and ephedrine; corticosteroids such as
prednisolone and adrenal stimulants such as ACTH may be
included.
[0063] For parenteral administration, fluid unit dosage forms are
prepared utilizing the compound and a sterile vehicle, and,
depending on the concentration used, can be either suspended or
dissolved in the vehicle. In preparing solutions the compound can
be dissolved in water for injection and filter sterilised before
filling into a suitable vial or ampoule and sealing.
[0064] Advantageously, adjuvants such as local anaesthetic, a
preservative and buffering agents can be dissolved in the vehicle.
To enhance the stability, the composition can be frozen after
filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same
manner, except that the compound is suspended in the vehicle
instead of being dissolved, and sterilisation cannot be
accomplished by filtration. The compound can be sterilised by
exposure to ethylene oxide before suspending in the sterile
vehicle. Advantageously, a surfactant or wetting agent is included
in the composition to facilitate uniform distribution of the
compound.
[0065] The compositions may contain from 0.1% to 99% by weight,
preferably from 10-60% by weight, of the active material, depending
on the method of administration.
[0066] Compounds of formula (i), or if appropriate a
pharmaceutically-acceptable salt thereof and/or a
pharmaceutically-accept- able solvate thereof, may also be
administered as a topical formulation in combination with
conventional topical excipients.
[0067] Topical formulations may be presented as, for instance,
ointments, creams or lotions, impregnated dressings, gels, gel
sticks, spray and aerosols, and may contain appropriate
conventional additives such as preservatives, solvents to assist
drug penetration and emollients in ointments and creams. The
formulations may contain compatible conventional carriers, such as
cream or ointment bases and ethanol or oleyl alcohol for
lotions.
[0068] Suitable cream, lotion, gel stick, ointment, spray or
aerosol formulations that may be used for compounds of formula (i)
or if appropriate a pharmaceutically-acceptable salt thereof are
conventional formulations well known in the art, for example, as
described in standard text books such as Harry's Cosmeticology
published by Leonard Hill Books, Remington's Pharmaceutical
Sciences, and the British and US Pharmacopoeias.
[0069] Suitably, the compound of formula (i), or if appropriate a
pharmaceutically-acceptable salt thereof will comprise from about
0.5 to 20% by weight of the formulation, favourably from about 1 to
10%, for example 2 to 5%.
[0070] The dose of the compound used in the treatment of the
invention will vary in the usual way with the seriousness of the
disorders, the weight of the sufferer, and the relative efficacy of
the compound. However, as a general guide suitable unit doses may
be 0.1 to 1000 mg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg,
for example 0.5, 1, 2, 3, 4 or 5 mg; and such unit doses may be
administered more than once a day, for example 2, 3, 4, 5 or 6
times a day, but preferably 1 or 2 times per day, so that the total
daily dosage for a 70 kg adult is in the range of about 0.1 to 1000
mg, that is in the range of about 0.001 to 20 mg/kg/day, such as
0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5 mg/kg/day,
for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2
mg/kg/day, and such therapy may extend for a number of weeks or
months.
[0071] When used herein the term "pharmaceutically-acceptable"
encompasses materials suitable for both human and veterinary
use.
[0072] The following Examples illustrate the invention.
[0073] Intermediate 1
2-Amino-3-nitroanisole
[0074] Tetrabutylammonium iodide (0.4 g), sodium hydroxide (4.0 g)
in water (40 ml) and iodomethane (3.4 ml) were added to
2-amino-3-nitrophenol (4.0 g) dissolved in tetrahydrofuran (80 ml)
at ambient temperature. This mixture was stirred overnight then
concentrated in vacuo. After pouring into water (200 ml) it was
extracted into ethyl acetate (2.times.200 ml) then washed with
aqueous sodium bicarbonate (100 ml) and saturated brine (100 ml).
The solution was dried over anhydrous magnesium sulphate, filtered
and evaporated in vacuo to afford the title compound as a dark
solid (4.4 g).
[0075] TLC R.sub.f 0.7 (50% ethyl acetate in hexane)
[0076] Intermediate 2
2,3-Diaminoanisole
[0077] 2-Amino-3-nitroanisole (4.3 g) was hydrogenated in ethyl
acetate (200 ml) using catalytic 10% palladium on charcoal under an
atmosphere of hydrogen at ambient temperature. Once complete the
reaction mixture was filtered through Celite and the filtrate
evaporated in vacuo to afford the title compound as a brown liquid
(3.60 g).
[0078] TLC R.sub.f 0.65 (ethyl acetate)
[0079] Intermediate 3
5-Methoxyquinoxaline
[0080] Glyoxal sodium bisulphite hydrate (10.0 g) in water (80 ml)
was warmed to 60.degree. C. then a solution of 2,3-diaminoanisole
(3.40 g) in ethanol (40 ml) was added. The stirred mixture was then
heated to 80.degree. C. for 1 h before addition of concentrated
hydrochloric acid (6 drops). Heating was continued for 1 h. It was
allowed to cool overnight, concentrated in vacuo and poured into
aqueous potassium carbonate (40 ml). Ethyl acetate (3.times.100 ml)
extracts were washed with water (100 ml) and saturated brine (50
ml) then dried over anhydrous magnesium sulphate, filtered and
evaporated in vacuo to afford the title compound as a yellow solid
(3.07 g).
[0081] TLC R.sub.f 0.40 (ethyl acetate)
[0082] Intermediate 4
8-Methoxyquinoxaline-5-carboxylic acid
[0083] A solution of bromine (0.76 ml) in methanol (10 ml) was
added over 15 minutes to 5-methoxyquinoxaline (2.3 g) in methanol
(50 ml) at -20.degree. C. under an inert atmosphere. After stirring
for 4 h the reaction mixture was stored at -20.degree. C.
overnight. It was poured into aqueous sodium metabisulphite (100
ml), basified with sodium bicarbonate and extracted into ethyl
acetate (3.times.100 ml). These extracts were washed with water
(100 ml) and saturated brine (50 ml) then dried over anhydrous
magnesium sulphate, filtered and evaporated in vacuo to afford a
brown solid (2.45 g). Purification by column chromatography using
50% ethyl acetate in hexane as eluent yielded an off-white solid
(0.46 g) as a mixture of the 5-bromo and 5,6-dibrominated products.
This solid, triphenylphosphine (0.5 g),
bis(triphenylphosphine)palladium (II) chloride (1.0 g) and
triethylamine (6 ml) were dissolved in tetrahydrofuran (200 ml) and
heated to 80.degree. C. in a Parr apparatus under an atmosphere of
carbon monoxide gas at 1380 kPa (200 psi). After 6 days, the
mixture was allowed to cool to ambient temperature and concentrated
in vacuo. It was basified to pH14 using 1M sodium hydroxide
solution and extracted with ethyl acetate (2.times.200 ml). These
extracts were back extracted with 1M sodium hydroxide solution
(2.times.100 ml) and the combined aqueous phases acidified to pH5
using glacial acetic acid. Ethyl acetate (2.times.200 ml) extracts
of this acidic aqueous phase were washed with water (100 ml) and
saturated brine (50 ml) then dried over anhydrous magnesium
sulphate, filtered and evaporated in vacuo to afford the title
compound as a solid (0.19 g).
[0084] TLC R.sub.f 0.20 (ethyl acetate)
[0085] Intermediate 5
4-Methoxy-2-trifluoromethylbenzimidazole
[0086] A solution of 2,3-diaminoanisole (1.0 g) in trifluoroacetic
acid (15 ml) was refluxed for 5 h and then stirred at room
temperature overnight. Excess trifluoroacetic acid was removed in
vacuo and the residue partitioned between ethyl acetate (50 ml) and
water (50 ml). The organic phase was washed with saturated sodium
bicarbonate solution (50 ml) and water (50 ml). Drying over
anhydrous sodium sulfate and removal of the solvent in vacuo gave a
brown residue. Purification by column chromatography eluting with
50% ethyl acetate in hexane gave the title compound as a yellow
solid (1.4 g).
[0087] TLC R.sub.f 0.64 (50% ethyl acetate in hexane)
[0088] Intermediate 6
2-(1-Hydroxyethyl)-4-methoxybenzimidazole
[0089] 2,3-Diaminoanisole (5.88 g) and lactic acid (5.6 ml) were
combined, treated with concentrated hydrochloric acid (45 ml) and
heated at 100.degree. C. for 18 h. The reaction was cooled to
0.degree. C., neutralised with ammonium hydroxide solution and
extracted with ethyl acetate (3.times.45 ml). The combined organic
layers were dried over magnesium sulphate, filtered and the
filtrate evaporated in vacuo and the residue purified by flash
chromatography on silica eluting with ethyl acetate to yield the
desired product as a reddish-brown solid (4.91 g).
[0090] TLC R.sub.f 0.125 (ethyl acetate)
[0091] Intermediate 7
2-Acetyl-4-methoxybenzimidazole
[0092] A solution of 2-(1-hydroxyethyl)-4-methoxybenzimidazole
(2.18 g) in acetic acid (8.5 ml) was heated at 100.degree. C. and
treated with a solution of chromium trioxide (0.85 g) in water (3
ml). After 10 minutes the reaction was poured into water (110 ml),
the precipitate was removed by filtration through a plug of Celite
and the product extracted with dichloromethane (3.times.100 ml).
The combined organic layers were dried over magnesium sulphate,
filtered, and evaporated in vacuo and to yield the desired product
as a light-brown solid (1.4 g).
[0093] TLC R.sub.f 0.6 (ethyl acetate)
[0094] Intermediate 8
7-Methoxy-3-methyl-2-trifluoromethylbenzimidazole
[0095] To a solution of 4-methoxy-2-trifluoromethylbenzimidazole
(1.4 g) in tetrahydrofuran (40 ml) under nitrogen was added sodium
hydride (0.32 g; 60% dispersion in oil). The mixture was stirred
for 20 minutes at room temperature before methyl iodide (1.35 g)
was added. Stirring was continued overnight. The reaction was
quenched by the addition of water (10 ml) and the solvent removed
in vacuo. Ethyl acetate (50 ml) was added and the organic layer
washed with saturated sodium bicarbonate solution (20 ml), water
(20 ml) and brine (20 ml). Drying over anhydrous magnesium sulfate
followed by the removal of the solvent in vacuo gave the title
compound (1.6 g) as an oil which solidified on standing.
[0096] TLC R.sub.f 0.75 (50% ethyl acetate in hexane)
[0097] The following compounds were prepared by a similar
procedure.
[0098] Intermediate 9
2-Acetyl-7-methoxy-3-methylbenzimidazole
[0099] Prepared from 2-acetyl-7-methoxybenzimidazole (0.5 g).
Purification by flash chromatography on silica eluting with 50%
ethyl acetate in hexane gave the title compound as a white solid
(0.24 g).
[0100] TLC R.sub.f 0.38 (50% ethyl acetate in hexane)
[0101] Intermediate 10
7-Methoxy-3-propyl-2-trifluoromethylbenzimidazole
[0102] Prepared from 4-methoxy-2-trifluoromethylbenzimidazole (2.4
g) and propyl bromide (3.02 ml). Purification by flash
chromatography on silica eluting with 15% ethyl acetate in hexane
gave the title compound as a white solid (2.03 g).
[0103] TLC R.sub.f 0.4 (20% ethyl acetate in hexane)
[0104] Intermediate 11
4-Bromo-7-methoxy-3-methyl-2-trifluoromethylbenzimidazole
[0105] To a solution of
7-methoxy-3-methyl-2-trifluoromethylbenzimidazole (1.4 g) in
chloroform (50 ml) under nitrogen was added N-bromosuccinimide (1.2
g). The mixture was stirred for 20 minutes before the reaction was
quenched by the addition of 5% sodium metabisulphite solution (50
ml) and the organic layer was separated. Washing with water (50
ml), drying over anhydrous magnesium sulphate and removal of the
solvent in vacuo gave an orange oil. Purification by flash
chromatography eluting with 50% ethyl acetate in hexane gave the
title compound as an orange solid (1.73 g).
[0106] TLC R.sub.f 0.79 (50% ethyl acetate in hexane)
[0107] The following compounds were prepared by a similar
procedure.
[0108] Intermediate 12
2-Acetyl-4-bromo-7-methoxy-3-methylbenzimidazole
[0109] Prepared from 2-acetyl-7-methoxy-3-methylbenzimidazole (0.24
g). Purification by flash chromatography on silica eluting with 50%
ethyl acetate in hexane gave the desired product as a white solid
(0.23 g).
[0110] TLC R.sub.f 0.5 (50% ethyl acetate in hexane)
[0111] Intermediate 13
4-Bromo-7-methoxy-3-propyl-2-trifluoromethylbenzimidazole
[0112] Prepared from
7-methoxy-3-propyl-2-trifluoromethylbenzimidazole (2.03 g).
Purification by flash chromatography on silica eluting with 15%
ethyl acetate in hexane gave the title compound as a white solid
(0.69 g).
[0113] TLC R.sub.f 0.4 (20% ethyl acetate in hexane)
[0114] Intermediate 14
7-Methoxy-3-methyl-2-trifluoromethylbenzimidazole-4-carboxylic
acid
[0115] A mixture of
4-bromo-7-methoxy-3-methyl-2-trifluoromethylbenzimidaz- ole (1.7
g), bis(triphenylphosphine)palladium (II) chloride (0.26 g),
triphenylphosphine (0.48 g) and triethylamine (7.7 ml) in
tetrahydrofuran (30 ml) and water (10 ml) were heated to 80.degree.
C. in a Parr apparatus under an atmosphere of carbon monoxide gas
at 1240 kPa (180 psi). After 3 days, the mixture was allowed to
cool to ambient temperature and concentrated in vacuo. It was
basified to pH14 using 1M sodium hydroxide solution and extracted
with ethyl acetate (2.times.50 ml). The aqueous phase acidified to
pH5 using glacial acetic acid. The resulting precipitate was
filtered off and washed with water to give the title compound (0.81
g) as an off white solid.
[0116] TLC R.sub.f 0.37 (50% ethyl acetate in hexane)
[0117] The following compounds were prepared by a similar
procedure.
[0118] Intermediate 15
2-Acetyl-7-methoxy-3-methylbenzimidazole-4-carboxylic acid
[0119] Prepared from
2-acetyl-4-bromo-7-methoxy-3-methylbenzimidazole. Purification by
flash chromatography on silica eluting with 50% ethyl acetate in
hexane gave the desired product as a white solid (1.38 g).
[0120] TLC R.sub.f 0.75 (50% ethyl acetate in hexane)
[0121] Intermediate 16
7-Methoxy-3-propyl-2-trifluoromethylbenzimidazole-4-carboxylic
acid
[0122] Prepared from
4-bromo-7-methoxy-3-propyl-2-trifluoromethylbenzimida- zole (0.69
g). Trituration with t-butyl methyl ether gave the title compound
as a white solid (0.29 g).
[0123] TLC R.sub.f 0.4 (50% ethyl acetate in hexane)
[0124] Intermediate 17
4-Bromo7-methoxy-2-trifluoromethylbenzimidazole
[0125] A solution of 7-methoxy-2-trifluoromethylbenzimidazole (5.0
g) in chloroform (100 ml) was cooled to 0.degree. C. and
N-bromosuccinimide (4.5 g) added. The mixture was stirred for 2 h.
It was then washed with 5% aqueous sodium metabisulphite (50 ml),
dried over magnesium sulphate, evaporated in vacuo and purified by
flash chromatography eluting with 25% ethyl acetate in hexane to
yield the title compound as a white solid (1.0 g).
[0126] TLC R.sub.f 0.29 (20% ethyl acetate in hexane)
[0127] Intermediate 18
4-Bromo-7-methoxy-3-(4-methoxybenzyl)-2-trifluoromethyl-benzimidazole
[0128] Sodium hydride (0.16 g; 60% dispersion in oil) was added to
a solution of 4-bromo-7-methoxy-2-trifluoromethylbenzimidazole (1.0
g) in N,N-dimethylformamide (20 ml). The mixture was stirred at
room temperature for 10 minutes before addition of 4-methoxybenzyl
chloride (0.56 ml) and catalytic tetrabutylammonium iodide. The
reaction was heated at 90.degree. C. for 6 h, then poured into
water (100 ml) and extracted with ethyl acetate (2.times.100 ml).
The combined organic phases were washed with water (100 ml) and
brine (50 ml), dried over magnesium sulphate, evaporated in vacuo
and purified by flash chromatography eluting with 33% ethyl acetate
in hexane to afford the title compound as a white solid (0.52
g).
[0129] TLC R.sub.f 0.31 (20% ethyl acetate in hexane)
[0130] Intermediate 19
7-Methoxy-3-(4-methoxybenzyl)-2-trifluoromethyl-benzimidazole-4-carboxylic
acid
[0131] A mixture of
4-bromo-7-methoxy-3-(4-methoxybenzyl)-2-trifluoromethy-
l-benzimidazole (520 mg), bis(triphenylphosphine)palladium (II)
chloride (90 mg), triphenylphosphine (110 mg) and triethylamine
(1.8 ml) in tetrahydrofuran (50 ml) and water (15 ml) were heated
to 80.degree. C. in a Parr apparatus under an atmosphere of carbon
monoxide gas at 1240 kPa (180 psi). Afer 5 days, the mixture was
allowed to cool to ambient temperature and concentrated in vacuo.
It was basified with 1M sodium hydroxide solution and extracted
with ethyl acetate (2.times.50 ml). The aqueous phase was acidified
to pH6 using glacial acetic acid and extracted with ethyl acetate
(2.times.75 ml). The combined extracts were dried over magnesium
sulphate and evaporated in vacuo to give the title compound as a
cream solid (310 mg).
[0132] TLC R.sub.f 0.12 (50% ethyl acetate in hexane)
[0133] Intermediate 20
2-Ethyl-4-hydroxybenzoxazole
[0134] A mixture of 2-aminoresorcinol hydrochloride (5.0 g) and
triethylorthopropionate (13.7 ml) was heated to 150.degree. C. for
2 h before being poured into a mixture of water (140 ml) and
ethanol (35 ml). The mixture was stirred vigorously for 30 minutes
at room temperature. The resulting precipitate was removed by
filtration and dried to give the title compound as a beige solid
(4.11 g).
[0135] TLC R.sub.f 0.40 (50% ethyl acetate in hexane)
[0136] Intermediate 21
4-Hydroxybenzoxazole
[0137] 2-Aminoresorcinol hydrochloride (2 g) and
triethylchloroformate (4.5 ml) were heated to reflux under nitrogen
for 3 h. After cooling to room temperature, the reaction mixture
was poured into a mixture of water (70 ml) and ethanol (20 ml). The
mixture was stirred vigorously for 30 minutes, then left to stand
at room temperature overnight. The beige precipitate which formed
was collected by filtration, and dried by azeotroping with toluene
to give the title compound as a beige solid (1.2 g).
[0138] Intermediate 22
2-Ethyl-4-methoxybenzoxazole
[0139] 2-Ethyl-4-hydroxybenzoxazole (4.17 g) was dissolved in
tetrahydrofuran (73 ml) at room temperature. Tetrabutylammonium
iodide (0.4 g) was added, followed by a solution of sodium
hydroxide (3.89 g) in water (40 ml). The mixture was stirred for 10
minutes before addition of iodomethane (3.13 ml). Stirring was then
continued overnight. The crude mixture was evaporated onto silica,
and purified by flash chromatography eluting with 25% then 50%
ethyl acetate in hexane to give the title compound as a straw
coloured liquid (3.05 g).
[0140] TLC R.sub.f 0.50 (50% ethyl acetate in hexane)
[0141] The following compound was prepared by a similar
procedure.
[0142] Intermediate 23
4-Methoxybenzoxazole
[0143] Prepared from 4-hydroxybenzoxazole to furnish the title
compound (90 mg) as a brown solid.
[0144] TLC R.sub.f 0.41 (50% ethyl acetate in hexane)
[0145] Intermediate 24
2(1- Hydroxyethyl)-4-methoxybenzoxazole
[0146] 4-Methoxybenzoxazole (6.0 g) was dissolved in
tetrahydrofuran (225 ml) and cooled to -78.degree. C. under
nitrogen. n-Butyllithium (26.5 ml of a 1.6M solution in hexanes)
was added, and the mixture stirred at -78.degree. C. for 30 minutes
before addition of magnesium bromide etherate (11.5 g). The
resulting heterogeneous mixture was stirred at -45.degree. C. for
15 minutes, and then cooled to -78.degree. C. A solution of
acetaldehyde (2.3 ml) was added from a pre-cooled syringe. The
mixture was stirred at -78.degree. C. for 3 h, then allowed to warm
to room temperature and stirred overnight. It was quenched with
aqueous sodium bicarbonate (50 ml, gradually) and the
tetrahydrofuran evaporated in vacuo. The residue was extracted with
dichloromethane (3.times.50 ml). The combined organic phases were
dried over magnesium sulphate, evaporated in vacuo and purified by
flash chromatography eluting with 30%-50% ethyl acetate in hexane
to afford the title compound as a brown solid (6.25 g).
[0147] TLC R.sub.f 0.14 (30% ethyl acetate in hexane)
[0148] Intermediate 25
2-Acetyl-4-methoxybenzoxazole
[0149] A solution of oxalyl chloride (0.25 ml) in dichloromethane
(6.5 ml) was cooled to -55.degree. C. under nitrogen. A solution of
dimethylsulphoxide (0.44 ml) in dichloromethane (1.3 ml) was added
dropwise, and the mixture stirred for 5 minutes at -55.degree. C.
before addition of a solution of
2-(1-hydroxyethyl)-4-methoxybenzoxazole (0.5 g) in dichloromethane
(2.5 ml). Stirring was continued for 15 minutes at -55.degree. C.,
then triethylamine (1.8 ml) was added The mixture was stirred at
-55.degree. C. for 5 minutes and was then allowed to warm to room
temperature. It was poured into water (25 ml) and the layers
separated. The aqueous phase was extracted with dichloromethane (20
ml). The combined organic phases were dried over magnesium
sulphate, evaporated in vacuo and purified by flash chromatography
eluting with 30% ethyl acetate in hexane to yield the title
compound as a white solid (350 mg).
[0150] TLC R.sub.f 0.45 (50% ethyl acetate in hexane)
[0151] Intermediate 26
4-Methoxy-2-(2-methyl-[1,3]-dioxolan-2-yl)benzoxazole
[0152] 2-Acetyl-4-methoxybenzoxazole (200 mg), p-toluenesulphonic
acid (239 mg), ethylene glycol (0.29 ml) and toluene (10 ml) were
heated to reflux under Dean-Stark condidions for 2 h. After cooling
to room temperature, the toluene was evaporated, and the residue
partitoned between water (20 ml) and ethyl acetate (20 ml). The
aqueous phase was extracted with ethyl acetate (20 ml). The
combined organic phases were washed with water (40 ml), aqueous
sodium bicarbonate (2.times.40 ml) and water (40 ml), dried over
magnesium sulphate, evaporated in vacuo and purified by flash
chromatography eluting with 30% ethyl acetate in hexane to yield
the title compound as a white solid (129 mg).
[0153] TLC R.sub.f 0.32 (30% ethyl acetate in hexane)
[0154] Intermediate 27
7-Bromo-2-ethyl-4-methoxybenzoxazole
[0155] 2-Ethyl-4-methoxybenzoxazole (2.81 g) was dissolved in
methanol (80 ml) under nitrogen and the solution cooled to
-78.degree. C. Bromine (0.73 ml) was added dropwise. The mixture
was allowed to warm gradually to room temperature and stirred for
3.5 h. The methanol was evaporated in vacuo and the residue
partitioned between ethyl acetate and aqueous sodium bicarbonate.
The combined organic phases were washed with 5% aqueous sodium
metabisulphite, evaporated onto silica and purified by flash
chromatography eluting with 25%-50% ethyl acetate in hexane to give
a mixture of the title compound and 2-ethyl-4-methoxybenzoxazole as
a pale yellow liquid (2.28 g).
[0156] TLC R.sub.f 0.50 (50% ethyl acetate in hexane)
[0157] Intermediate 28
2-Ethyl-4-methoxybenzoxazole-7-carboxylic acid
[0158] A mixture of 7-bromo-2-ethyl-4-methoxybenzoxazole (0.7 g),
triphenylphosphine (0.273 g)
bis(triphenylphosphine)palladium(II)chloride (0.125 g) and
triethylamine (3.9 ml) in tetrahydrofuran (19 ml) and water (6.2
ml) were heated to 80.degree. C. in a Parr apparatus under an
atmosphere of carbon monoxide gas at 140 psi for 3 days. The
mixture was then allowed to cool to ambient temperature and
concentrated in vacuo. It was basified to pH14 using 1M sodium
hydroxide solution and extracted with ethyl acetate (2.times.50
ml). The aqueous phase was acidified to pH5 using glacial acetic
acid and extracted with dichloromethane. The combined
dichloromethane extracts were dried (MgSO.sub.4) and evaporated in
vacuo to give the title compound as a beige solid (0.40 g).
[0159] TLC R.sub.f 0.30 (50% ethyl acetate in hexane)
[0160] Intermediate 29
7-Bromo-4-methoxy-2-(2-methyl-[1,3]-dioxolan-2-yl)benzoxazole
[0161] 4-Methoxy-2-(2-methyl-[1,3]-dioxolan-2-yl)benzoxazole (129
mg), N-bromosuccinimide (107 mg) and acetonitrile (5 ml) were
combined and stirred at room temperature under nitrogen for 4 h.
The mixture was partitioned between water (20 ml) and ethyl acetate
(20 ml). The aqueous phase was extracted with ethyl acetate (20 ml)
The combined organic phases were washed with water (2.times.50 ml),
dried over magnesium sulphate, evaporated in vacuo and purified by
flash chromatography eluting with 30% ethyl acetate in hexane to
yield the title compound as a white solid (95 mg).
[0162] TLC R.sub.f 0.41 (30% ethyl acetate in hexane)
[0163] The following compound was prepared by a similar
procedure.
[0164] Intermediate 30
7-Bromo-4-methoxybenzoxazole
[0165] Prepared from 4-methoxybenzoxazole to afford the title
compound (635 mg).
[0166] TLC R.sub.f 0.51 (30% ethyl acetate in hexane)
[0167] Intermediate 31
4-Methoxy-2-(2-methyl-[1,3]-dioxolan-2-yl)benzoxazole-7-carboxylic
acid
[0168]
7-Bromo-4-methoxy-2-(2-methyl-[1,3]-dioxolan-2-yl)benzoxazole (480
mg), palladium acetate (34 mg), 1,3-bis(diphenylphosphino)propane
(126 mg), triethylamine (0.21 ml), water (15 ml) and
tetrahydrofuran (30 ml) were combined and heated to 90.degree. C.
in a Parr apparatus under 1035 kPa (150 psi) of carbon monoxide for
3 days. After cooling to room temperature, the tetrahydrofuran was
evaporated in vacuo. The residue was partitioned between ethyl
acetate (50 ml) and water (50 ml). The aqueous layer was extracted
with ethyl acetate (50 ml). The combined organic extracts were
dried over magnesium sulphate, evaporated in vacuo and purified by
flash chromatography eluting with ethyl acetate to yield the title
compound as a white solid (190 mg).
[0169] TLC R.sub.f 0.51 (ethyl acetate)
[0170] Intermediate 32
4-Methoxybenzoxazole-7-carboxylic acid
[0171] 7-Bromo-4-methoxybenzoxazole (630 mg), triethylamine (3.85
ml), triphenylphosphine (290 mg), bis(triphenylphosphine)palladium
chloride (88 mg), water (20 ml) and tetrahydrofuran (40 ml) were
combined and heated to 90.degree. C. in a Parr apparatus under 1035
kPa (150 psi) of carbon monoxide for 3 days. After cooling to room
temperature, the tetrahydrofuran was evaporated. The residue was
partitioned between ethyl acetate (50 ml) and water (50 ml). The
aqueous phase was acidified to pH4 with acetic acid, and the layers
separated. The aqueous phase was extracted with ethyl acetate
(2.times.30 ml) followed by dichloromethane (2.times.30 ml). The
combined organic phases were dried over magnesium sulphate and
evaporated in vacuo. Purification of the residue by flash
chromatography eluting with ethyl acetate and trituration with
diethyl ether afforded the title compound as a white solid (125
mg). On standing, a white solid precipitated in the water layer
which was removed by filtration and dried in vacuo at 45.degree. C.
for 1 hour to give a further portion of the title compound as a
white solid (49 mg).
[0172] TLC R.sub.f 0.50 (ethyl acetate)
EXAMPLE 1
8-Methoxyquinoxaline-5-[N-(3,5-dichloropyrid-4-yl)]carboxamide
[0173] 8-Methoxyquinoxaline-5-carboxylic acid (0.19 g) dissolved in
dichloromethane (16 ml) under an inert atmosphere was treated with
oxalyl chloride (0.3 ml) then 2 drops of N,N-dimethylformamide and
stirred at ambient temperature overnight. The reaction mixture was
evaporated in vacuo and azeotroped with dry toluene (2.times.15 ml)
to afford the acid chloride dihydrochloride as a brown solid (0.3
g). A solution of this solid in dry N,N-dimethylformamide (10 ml)
was added at 60.degree. C. to a mixture of
4-amino-3,5-dichloropyridine (0.16 g), sodium hydride (0.15 g; 60%
dispersion in oil) and N,N-dimethylformamide (10 ml) that had
already been stirred at ambient temperature for 1 h. After 2 h the
mixture was allowed to cool overnight before evaporating in vacuo.
The residue was filtered through a pad of silica using hot ethyl
acetate and the filtrate evaporated in vacuo to yield another
residue. This was purified by column chromatography using 10%
methanol in ethyl acetate as eluant to afford the title compound as
an off-white solid (0.09 g).
[0174] TLC R.sub.f 0.65 (10% methanol in ethyl acetate)
[0175] mp 205-208.degree. C.
[0176] The following compound was prepared by a similar
procedure.
EXAMPLE 2
2-Acetyl-7-methoxy-3-methylbenzimidazole-4-[N-(pyridin-4-yl)]carboxamide
[0177] Prepared from
2-acetyl-7-methoxy-3-methylbenzimidazole-4-carboxylic acid (0.50 g)
and 4-aminopyridine (0.18 g). Purification by flash chromatography
on silica eluting with 10% methanol in ethyl acetate gave the title
compound as an off-white solid (0.10 g).
[0178] TLC R.sub.f 0.31 (10% methanol in ethyl acetate)
[0179] mp 274-275.degree. C.
EXAMPLE 3
7-Methoxy-3-methyl-2-trifluoromethylbenzimidazole4-[N-(3,5-dichloropyrid-4-
-yl)]carboxamide
[0180]
7-Methoxy-3-methyl-2-trifluoromethylbenzimidazole-4-carboxylic acid
(0.40 g) dissolved in dichloromethane (20 ml) under nitrogen was
treated with oxalyl chloride (0.28 ml) then 2 drops of
N,N-dimethylformamide and stirred at ambient temperature overnight.
The reaction mixture was evaporated in vacuo to afford the acid
chloride hydrochloride as a brown solid. A solution of this solid
in dry N,N-dimethylformamide (long) was added at ambient
temperature to a mixture of 4-amino-3,5-dichloropyridine (0.29 g),
sodium hydride (0.30 g; 60% dispersion) and N,N-dimethylformamide
(10 ml) that had already been stirred at ambient temperature for 1
h. After 2 h the mixture was allowed to cool overnight before
evaporating in vacuo. The residue was purified by column
chromatography using 50% ethyl acetate in hexane as eluant to
afford the title compound as a white solid (0.16 g).
[0181] TLC R.sub.f 0.34 (50% ethyl acetate in hexane)
[0182] mp 228-229.degree. C.
[0183] The following compounds were prepared in a similar
manner.
EXAMPLE 4
7-Methoxy-3-propyl-2-trifluoromethylbenzimidazole-4-[N-(3,5-dichloropyridi-
n-4-yl)]carboxamide
[0184] Prepared from
7-methoxy-3-propyl-2-trifluoromethylbenzimidazole-4-c- arboxylic
acid (0.28 g) and 4-amino-3,5-dichloropyridine (0.18 g).
Purification by flash chromatography on silica eluting with 40%
ethyl acetate in hexane gave the title compound as a white solid
(0.006 g).
[0185] TLC R.sub.f 0.21 (40% ethyl acetate in hexane)
[0186] mp 246-247.degree. C.
EXAMPLE 5
2-Acetyl-7-methoxy-3-methylbenzimidazole-4-[N-(3,5-dichloropyrid-4-yl)]car-
boxamide
[0187] Prepared from
2-acetyl-7-methoxy-3-methylbenzimidazole-4-carboxylic acid (1.38
g). Purification by flash chromatography eluting with 10% methanol
in dichloromethane yielded the title compound (0.75 g) as a beige
solid.
[0188] TLC R.sub.f 0.5 (10% methanol in dichloromethane)
[0189] m.p. 290-291.degree. C.
EXAMPLE 6
2-Ethyl-4-methoxybenzoxazole-7-[N-(4-pyridyl)]carboxamide
[0190] Oxalyl chloride (0.32 ml) was added to a solution of
2-ethyl-4-methoxybenzoxazole-7-carboxylate (0.40 g) in
dichloromethane (20 ml) at room temperature under nitrogen. After
stirring for 10 minutes, dry N,N-dimethylformamide (2 drops) was
added. Stirring was continued overnight to give a yellow solution
which was evaporated to dryness in vacuo. The residue was dissolved
in dichloromethane (20 ml). Triethylamine (0.53 ml) was added,
followed by 4-aminopyridine (0.20 g), and the mixture stirred at
room temperature overnight. It was evaporated onto silica, and
purified by flash chromatography eluting with dichloromethane then
10% methanol in dichloromethane to give the title compound as a tan
solid (0.08 g).
[0191] TLC R.sub.f 0.45 (10% methanol in ethyl acetate)
[0192] mp 140-142.degree. C.
EXAMPLE 7
2-Ethyl-4-methoxybenzoxazole-7-[N(3,5-dichloropyrid-4-yl)]carboxamide
[0193] 2-Ethyl-4-methoxybenzoxazole-7-carboxylate (1.24 g),
4-dimethylaminopyridine (catalytic), 4-nitrophenol (1.17 g), and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.6 g)
in dichloromethane (60 ml) were stirred at room temperature for 48
h. The mixture was evaporated onto silica and chromatographed,
eluting with 50% ethyl acetate in hexane, to yield 4-nitrophenyl
2-ethyl-4-methoxybenzoxaz- ole-7-carboxylate.
4-Amino-3,5-dichloropyridine (0.57 g) was dissolved in
N,N-dimethylformamide (20 ml) at room temperature under nitrogen.
Sodium hydride (0.20 g; 60% dispersion) was added, and the mixture
stirred for 5 h before addition of the 4-nitrophenyl ester (1.2 g)
and stirred for a further 18 h. The reaction mixture was evaporated
onto silica and and purified by flash chromatography eluting with
50% ethyl acetate in hexane to separate the title compound as a
white solid (0.44 g).
[0194] TLC R.sub.f 0.20 (50% ethyl acetate in hexane)
[0195] mass spectrum (CI) [M+H].sup.+ observed
EXAMPLE 8
2-Ethyl-4-methoxybenzoazole-7-[N-(3,5-dichloropyridin-4-yl-N-oxide)]carbox-
amide
[0196] A solution of
2-ethyl-4-methoxybenzoxazole-7-[N-(3,5-dichloropyridi-
n-4-yl)]carboxamide (0.05 g) in chloroform (10 ml) was treated with
36-40% peracetic acid in acetic acid (0.3 ml) and stirred for 14
days at room temperature. The reaction mixture was partitioned
between dichloromethane (20 ml) and water (20 ml) The organic layer
was separated, dried over magnesium sulphate, filtered and the
filtrate evaporated in vacuo. Purification by flash chromatography
on silica eluting with 10% methanol in ethyl acetate gave the
desired product as a white solid (0.018 g).
[0197] TLC R.sub.f 0.38 (10% methanol in ethyl acetate)
[0198] mp 201-203.degree. C.
EXAMPLE 9
4-Methoxybenzoxazole-7-[N-(3,5-dichloropyridin-4-yl)]carboxamide
[0199] A mixture of 4-methoxybenzoxazole-7-carboxylic acid (0.16
g), dimethylaminopyridine (catalytic), 4-nitrophenol (0.17 g) and
1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g)
in dichloromethane (30 ml) was stirred at room temperature under
nitrogen overnight. The mixture was diluted with dichloromethane
(20 ml) and washed with water (2.times.50 ml). The combined organic
phases were dried over magnesium sulphate and evaporated in vacuo
to give 4-nitrophenyl 4-methoxybenzoxazole-7-carboxylate.
4-Amino-3,5-dichloropyridine (0.15 g) was dissolved in
N,N-dimethylformamide (5 ml) at room temperature under nitrogen.
Sodium hydride (40 mg; 60% disopersion in oil) was added, and the
mixture stirred for 1 h before addition of the 4-nitrophenyl ester
(0.26 g) in N,N-dimethylformamide (20 ml). After stirring for 60 h,
the N,N-dimethylformamide was evaporated in vacuo, and the residue
partitioned between ethyl acetate (40 ml) and water (40 ml). The
combined organic phases were washed with water (2.times.40 ml),
dried over magnesium sulphate, evaporated onto silica and purified
by flash chromatography eluting with 50% ethyl acetate in hexane)
to yield the title compound as a white solid (51 mg).
[0200] TLC R.sub.f 0.19 (50% ethyl acetate in hexane)
[0201] mp 193-194.5.degree. C.
[0202] The following compounds were prepared by a similar
procedure.
EXAMPLE 10
7-Methoxy-3-(4-methoxybenzyl)-2-trifluoromethylbenzimidazole-4-[N-(3,5-dic-
hloropyridin-4-yl)]carboxamide
[0203] Prepared from
7-methoxy-3-(4-methoxybenzyl)-2-trifluoromethylbenzim-
idazole-4carboxylic acid to furnish the title compound (140 mg) as
a white solid.
[0204] TLC R.sub.f 0.35 (50% ethyl acetate in hexane)
[0205] mp 184.5-186.degree. C.
EXAMPLE 11
2-(2-Methyl-[1,3]dioxolan-2-yl)-4-methoxybenzoxazole-7-[N-(3,5-dichloropyr-
idin-4-yl)]carboxylate
[0206] Prepared from
2-(2-methyl-[1,3]dioxolan-2-yl)-4-methoxybenzoxazole-- 7-carboxylic
acid to yield the title compound (58 mg) as a white solid.
[0207] TLC R.sub.f 0.61 (ethyl acetate)
[0208] mp 155-157.degree. C.
EXAMPLE 12
N-(3,5-Dichloropyrid-4-yl)-7-methoxy-2-trifluoromethylbenzimidazole-4-carb-
oxamide
[0209]
7-methoxy-3-(4-methoxybenzyl)-2-trifluoromethylbenzimidazole-4-[N-(-
3,5-dichloropyrid-4-yl)]carboxamide (50 mg) was stirred in
trifluoroacetic acid (3 ml) for 2 h at room temperatire. Excess
trifluoroacetic acid was removed in vacuo, and the residue
partitioned between ethyl acetate (25 ml) and aqueous sodium
bicarbonate (25 ml). The aqueous phase was extracted with ethyl
acetate (25 ml). The combined organic phases were dried over
magnesium sulphate and evaporated in vacuo to give a solid which
was triturated with diethyl ether to give the title compound as a
cream solid (19 mg).
[0210] TLC R.sub.f 0.30 (50% ethyl acetate in hexane)
[0211] mp 300-301.degree. C.
EXAMPLE 13
2-(1-Hydroxyimino)ethyl-7-methoxy-3-methyl-benzimidazole-4-[N-(3,5-dichlor-
opyridyl)]carboxamide
[0212] A mixture of
2-acetyl-7-methoxy-3-methylbenzimidazole-4-[N-(3,5-dic-
hloropyrid-4yl)]carboxamide (0.60 g), hydroxylamine hydrochloride
(1.05 g) and pyridine (1.22 ml) in toluene (40 ml) was heated at
reflux under Dean-Stark conditions for 21 h. The solvent was
evaporated in vacuo and the residue was triturated with water and
filtered off. The precipitate was dried in vacuo to furnish the
title compound (0.57 g) as a beige solid.
[0213] m.p. 272-273.degree. C.
[0214] Mass spectrum [M+H].sup.+ observed
EXAMPLE 14
3-Methyl-2-(1-(2-methylthiazol-4-ylmethoxy)iminoethyl)-7-methoxybenzimidaz-
ole-4-[N-(3,5-dichloropyrid-4-yl)]carboxamide
[0215] Sodium hydride (60%, 43 mg) was added to a solution of
2-(1-hydroxyimino)ethyl-7-methoxy-3-methylbenzimidazole-4-[N-(3,5-dichlor-
opyridyl)]carboxamide (200 mg) in dimethylformamide (20 ml) at room
temperature under an inert atmosphere. After 1 h,
4-chloromethyl-2-methyl- thiazole (217 mg) and dimethylformamide (5
ml) were added and stirring was continued at room temperature for
18 h. The reaction was quenched by the addition of water (25 ml)
and extracted into ethyl acetate (3.times.25 ml). The combined
organic phases were dried (magnesium sulphate), filtered and
evaporated onto silica gel. Purification by flash chromatography
eluting with ethyl acetate afforded the title compound (28 mg) as a
white solid.
[0216] m.p. 220-221.degree. C.
[0217] Mass spectrum [M+H].sup.+ observed
[0218] The following compound was prepared in a similar manner.
EXAMPLE 15
3Methyl-2-[1-(3-dimethylaminopropyloxy)iminoethyl]-7-methoxybenzimidazole--
4-[N-(3,5-dichloropyrid-4-yl)carboxamide
[0219] Prepared using
2-(1-hydroxyimino)ethyl-7-methoxy-3-methylbenzimidaz-
ole-4-[N-(3,5-dichloropyridyl)]carboxamide (330 mg) and
N,N-dimethylaminopropyl chloride hydrochloride (383 mg).
Purification by flash chromatography eluting with 20% methanol in
dichloromethane yielded the title compound (96 mg) as an off-white
solid.
[0220] TCR R.sub.f 0.25 (20% methanol in dichloromethane)
[0221] m.p. 186-187.degree. C.
[0222] Assay Methods
[0223] The assays used to confirm the phosphodiesterase IV
inhibitory activity of compounds of formula (i) are standard assay
procedures as disclosed by Schilling et al, Anal. Biochem. 216:154
(1994), Thompson and Strada, Adv. Cycl. Nucl. Res. 8:119 (1979) and
Gristwood and Owen, Br. J. Pharmacol. 87:91P (1986).
[0224] Compounds of formula (i) have exhibited activity at levels
consistent with those believed to be useful in treating
phosphodiesterase IV-related disease states in those assays.
[0225] The ability of compounds of formula (i) to inhibit TNF
production in human monocytes is measured as follows. Peripheral
blood mononuclear cells are prepared from freshly taken blood by
standard procedures. Cells are plated out in RPMII640+1% foetal
calf serum in the presence and absence of inhibitors. LPS (100
ng/ml) is added and cultures are incubated for 22 h at 37.degree.
C. in an atmosphere of 95% air/5% CO.sub.2. Supernatants are tested
fbr TNF.alpha. by ELISA using commercially available kits.
[0226] In vivo activity in a skin eosinophilia model is determined
by using the methods described by Hellewell et al, Br. J.
Pharmacol. 111:811 (1994) and Br. J. Pharmacol. 110:416 (1993).
Activity in a lung model is measured using the procedures described
by Kallos and Kallos, Int. Archs. Allergy Appl. Immunol. 73:77
(1984), and Sanjar et al, Br. J. Pharmacol. 99:679 (1990).
[0227] An additional lung model, which allows measurement of
inhibition of the early and late-phase asthmatic responses and also
the inhibition of airway hyperreactivity, is described by Broadley
et al, Pulmonary Pharmacol. 7:311 (1994), J. Immunological Methods
190:51 (1996) and British J. Pharmacol. 116:2351 (1995). Compounds
of the invention show activity in this model.
* * * * *